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Biomedical subjects

D Goldblatt

Publications and source records attributed to D Goldblatt.

At least 19 recordsLinked to original sources
PubMed2006

Correlation of molecular characteristics, isotype, and in vitro functional activity of human antipneumococcal monoclonal antibodies.

Structure-function correlations of pneumococcal antibodies are important in predicting how changes in the pneumococcus (Pnc)-specific B-cell repertoire will influence humoral immunity against invasive Pnc disease. Using a unique panel of human hybridomas derived from memory B cells after pneumococcal conjugate vaccination, we analyzed the structure-function relationship of nine monoclonal antibodies (MAbs) reactive to Pnc polysaccharides. The avidities of the antibodies correlated with the avidity of donor immune serum (R, 0.7; P < 0.025), and this relationship was particularly strong for immunoglobulin A clones (R, 1; P < 0.0005), suggesting that the MAbs may represent important clones contributing to serological memory. Common heavy-light chain combinations and amino acid replacement mutations were seen for clones with the same serospecificity from different individuals. The two highest-avidity MAbs used Vh3-48, and two MAbs with the same serospecificity, using the same V gene pairings (Vh3-7 and Vk2A17), had similar avidities, suggesting that canonical V gene use makes an important contribution to avidity. Although all clones had mutation levels consistent with their being derived from memory B cells, low levels of replacement mutation were associated with high avidities. This relationship was strongest for Vh genes (R, 0.8; P < 0.01). Opsonophagocytosis was demonstrated for all clones, and there was a trend toward clones using canonical genes with low levels of mutation having high opsonophagocytic activities (R, 0.5). These data suggest that the use of canonical genes in the Pnc antibody response is associated with highly functional antibodies and that most somatic mutations seen in these genes are not antigen selected.

Amino Acid Sequence↗
PubMed2004

Responses to a fourth dose of Haemophilus influenzae type B conjugate vaccine in early life.

OBJECTIVE: To describe the immune response of preterm infants, with a reduced response to primary Haemophilus influenzae type B (Hib) immunisation, to a fourth dose of Hib conjugate vaccine given in early life. DESIGN: Prospective observational study. SETTING: Five Wessex Neonatal Units. PATIENTS: Infants born at < 32 weeks and immunised with three doses of combined acellular pertussis-Hib vaccine, with a Hib IgG geometric mean concentration (GMC) < 1.0 microg/ml after these primary immunisations. INTERVENTIONS: An additional fourth dose of Hib conjugate vaccine given before 1 year of age. Blood taken to assess Hib IgG concentration and avidity after immunisation. MAIN OUTCOME MEASURES: Hib IgG GMC and avidity index. RESULTS: Ninety six infants (mean gestational age at birth 29.1 weeks) received a fourth dose of Hib at a mean age of 7.8 months. Hib IgG GMC after the primary immunisations was 0.17 microg/ml (95% confidence interval (CI) 0.14 to 0.20) rising to 4.68 microg/ml (95% CI 3.36 to 6.57) after the fourth dose (p < 0.0001). The IgG response to the fourth dose correlated positively with the response after the primary immunisations (p < 0.001). Hib IgG geometric mean avidity index (GMAI) after the primary immunisations was 30.87 (95% CI 20.40 to 46.73). This increased to 124.73 (95% CI 109.93 to 141.51) after the fourth dose (p < 0.0001). CONCLUSION: Preterm infants with very low IgG responses to Hib after primary immunisations with a combined acellular pertussis-Hib vaccine mount a good response to a fourth dose of Hib. This study suggests that all infants will benefit from a fourth dose of Hib, regardless of the age at which it is given.

Haemophilus Infections↗
PubMed2003

Risk of relapse after meningococcal C conjugate vaccine in nephrotic syndrome.

In November, 1999, all children under age 18 years in the UK were offered immunisation with the newly introduced meningococcal C conjugate vaccine (MCCV). In a cohort of 106 patients with nephrotic syndrome, there were 63 relapses during the 12 months before vaccination, and 96 during the equivalent period postvaccination (p=0.009). The relapse rate of nephrotic syndrome increased significantly after administration of MCCV. Whether to vaccinate such children needs to be carefully considered.

Ambulatory Care↗
PubMed2003

Impact of nutritional status on antibody responses to different vaccines in undernourished Gambian children.

AIM: To test the efficacy of T-cell-dependent and T-cell-independent vaccines in rural Gambian children suffering from a range of energy/protein and micronutrient deficiencies. METHODS: Nutritional status (anthropometry, haemoglobin, plasma leptin and micronutrient status) and response to two vaccinations (23 valent pneumococcal capsular polysaccharide vaccine, Pneumovax and the Human Diploid-Cell Rabies Vaccine) were assessed in 472 children aged 6 1/2 h to 9 1/2 y. RESULTS: Anthropometry and micronutrient status (as z-scores against European reference values) indicated a range from moderate to severe levels of undernutrition [mean (interquartile range): weight-for-age z-score -1.58 (-2.18 to -0.95); height-for-age z-score -0.94 (-1.51 to -0.35); body-mass-index-for-age z-score -1.43 (-2.05 to -0.84); mid-upper arm circumference -1.41 (-1.72 to -1.13); leptin -1.06 (-1.10 to -1.03); haemoglobin (Hb) -0.30 (-1.18 to 0.79); zinc -1.29 (-2.42 to -0.55); vitamin C -0.01 (-1.18 to 1.15); retinol -1.33 (-1.97 to -0.77)]. A seasonal effect was observed in haemoglobin levels and in all micronutrients (with the exception of zinc and retinol) and in the response to vaccination. After adjusting for seasonality, age and gender, no consistent associations were found between any of the measures of nutritional status and the effectiveness of seroconversion to either of the vaccines. CONCLUSION: The successful short-term seroconversion to whole inactivated viral and bacterial polysaccharide vaccines indicates that the processes leading to antibody secretion remain intact over a wide range of single and combined nutrient deficiencies.

Antibody Formation↗
PubMed2003

Effect of a fourth Haemophilus influenzae type b immunisation in preterm infants who received dexamethasone for chronic lung disease.

AIM: To assess whether a fourth Hib polysaccharide-tetanus protein conjugate vaccine (PRP-T) would improve antibody response in preterm infants previously treated with dexamethasone for chronic lung disease. METHODS: In a pilot study 12 infants born at less than 30 weeks gestation who had received corticosteroids were given a supplementary Hib dose six weeks after completion of the primary immunisation course. Serum samples obtained before and at eight weeks following the fourth Hib dose were analysed for total level and avidity of anti-PRP antibody. RESULTS: There was no significant increase in the geometric mean titre (GMT) of anti-PRP antibody resulting from the fourth Hib immunisation (GMT: pre 2.35 micro g/ml, post 2.24 micro g/ml, p = 0.79). A subgroup of six infants had subprotective antibody levels (<1.0 micro g/ml) after the primary immunisation course, which remained subprotective following the extra Hib immunisation. Despite the poor response in total antibody level, the study group showed a significant rise in PRP specific IgG avidity following the fourth immunisation (GMAI: pre 0.076, post 0.138, p = 0.043). CONCLUSION: An additional Hib immunisation given to recently steroid treated preterm infants six weeks after completion of the primary schedule did not augment primary immunogenicity. However, increasing avidity may imply successful priming and long term immunity to Hib.

Antibodies, Viral↗
PubMed2002

Neonatal dendritic cells are intrinsically biased against Th-1 immune responses.

Dendritic cells (DCs) were derived from human peripheral blood monocytes or cord blood monocytes cultured in the presence of IL-4 and GM-CSF. Adult and cord DCs were observed to have comparable immature phenotypes. However, the increase in surface expression of HLA-DR and CD86 after addition of LPS was significantly attenuated in cord DCs, with CD25 and CD83 expression also markedly reduced. Cord DCs were also unable to produce IL-12p70, failed to down-regulate expression of the chemokine receptor CCR5 and induced lower levels of IFN-gamma production from allogeneic naive CD4+ T cells than their adult counterparts. In contrast, the kinetics of the production of TNF-alpha and IL-10 in response to LPS stimulation was comparable to adult DCs. The reduced ability of cord DCs to attain a fully mature adult phenotype, and to activate naive CD4+ T cells to produce IFN-gamma, suggests that they are intrinsically preprogrammed against the generation of Th-1 immune responses.

Adult↗
PubMed2002

Increased expression of interleukin-13 but not interleukin-4 in CD4+ cells from patients with the hyper-IgE syndrome.

Hyper IgE syndrome (HIES) is a rare immunodeficiency disorder characterized mainly by high levels of polyclonal IgE in serum and recurrent staphylococcal abscesses of the skin and lungs. The raised IgE levels have led researchers to study the synthesis of cytokines that regulate switching of immunoglobulin production towards IgE such as interleukin-4 (IL-4), IL-12 and interferon-gamma (IFN)-gamma. However, the role of IL-13 in the disease pathogenesis has not been investigated extensively. In this study, we investigated intracellular expression of IL-4 and IL-13 in mononuclear cells and CD4+ cells isolated from patients with HIES and healthy controls. Cells were stained intracellularly with antibodies directed against IL-4 and IL-13 and analysed by flow cytometry before and after activation with PMA and calcium ionophore. The mean proportion of resting or activated IL-4 and IL-13 expressing mononuclear cells were comparable in the two groups as well as the proportion of IL-4 expressing CD4+ cells. In contrast, the mean proportion of IL-13 expressing CD4+ cells was increased significantly in patients with HIES in both the resting and the activated state compared to healthy controls. We conclude that increased expression of IL-13 in CD4+ cells from patients with HIES could account, at least partly, for raised IgE levels in those individuals.

CD4-Positive T-Lymphocytes↗
PubMed2002

A direct comparison of the antigen-specific antibody profiles of intravenous immunoglobulins derived from US and UK donor plasma.

BACKGROUND AND OBJECTIVES: Intravenous immunoglobulin (IVIG) is used in a range of immunodeficiency states that require a broad spectrum of protective antibodies to a range of common pathogens. A comparison of the antigen-specific antibody profile of preparations of an IVIG (Vigam) derived from US and UK sourced plasma was performed, and these preparations were also compared with three other IVIG products from different manufacturers. MATERIALS AND METHODS: Antibodies against a range of bacterial and viral pathogens were measured by immunoassay. RESULTS: Similar profiles were found for Vigam made from UK and US source plasma and also for the other three IVIGs tested, but some specific differences were observed. CONCLUSIONS: IVIG preparations have a similar therapeutic spectrum of antibodies when prepared from plasma sourced either from the UK or the US.

Antibodies, Bacterial↗
PubMed2001

Immune response of premature infants to meningococcal serogroup C and combined diphtheria-tetanus toxoids-acellular pertussis-Haemophilus influenzae type b conjugate vaccines.

To determine the immune response of premature infants to meningococcal serogroup C capsular polysaccharide (MCC) and combined diphtheria-tetanus toxoids-acellular pertussis-Haemophilus influenzae type b (DTaP-Hib) conjugate vaccines, 105 infants born at <32 weeks' gestation had Hib IgG geometric mean concentrations (GMCs) and MCC serum bactericidal antibody (SBA) geometric mean titers (GMTs) measured 1 month after the third immunization. Term infants served as control subjects. Premature infants had Hib GMCs of 0.27 microg/mL, with 21% achieving GMCs >1.0 microg/mL, compared with 0.81 microg/mL and 46% in term infants (P<.001 and P=.003, respectively). The MCC SBA GMT was 398, with 99% achieving an SBA > or =8, compared with 380 and 98% in term infants (P=.84 and P=1.0, respectively). Hib IgG was associated with age at third immunization (P<.001). When combined with the DTaP vaccine used in this study, the Hib GMC of premature infants was extremely low. The SBA GMT to MCC was similar to that of term infants.

Antibodies, Viral↗
PubMed2001

Influence of prior meningococcal C polysaccharide vaccination on the response and generation of memory after meningococcal C conjugate vaccination in young children.

To determine whether the immunological hyporesponsiveness induced by meningococcal AC polysaccharide (MACP) vaccines can be overcome by meningococcal C conjugate (MCC) vaccine in young children, serum bactericidal antibody (SBA) serogroup C-specific IgG and IgG avidity indices were measured in young children who received MACP vaccine, followed 7 months later by MCC vaccine, and their responses were compared with those in age-matched MACP-naive control children, who received a single dose of MCC vaccine. For children <1 year of age at MACP vaccination, the SBA geometric mean titer (GMT) after MCC vaccination was lower (P=.022) and proportions with SBA titers <8 (P=.0083) or <128 (P=.0091) were higher than those in the control children. For older children, there was no difference in the SBA GMTs between the study and control groups (P>.5) or in the proportion with SBA titers <8 (P=1.00) or <128 (P=.98). No increase in avidity occurred after MACP vaccination, whereas avidity increased significantly 1 month after MCC vaccination, with a further increase at 6 months, which indicates that the induction of immunological memory was not impaired.

Age Factors↗
PubMed2001

Clinical relevance of lower Hib response in DTPa-based combination vaccines.

Combination vaccines are essential to enable administration of all the required antigens in routine infant immunisation schedules at any single visit. Some combinations of diphtheria-tetanus-acellular pertussis (DTPa) with Haemophilus influenzae type b (Hib) conjugate vaccines have been shown to result in lower Hib titres than when Hib is administered separately. While confirming that a primary series with a DTPa-HBV-IPV/Hib combination gives lower antibody levels than separate Hib conjugates, we show that the nature (isotype and IgG subclasses) and function (avidity and opsonic activity) of the antibodies are the same, and immunologic memory is induced. It is likely therefore that the DTPa-HBV-IPV/Hib combination will be efficacious against Hib disease.

Antibodies, Bacterial↗
PubMed2001

A messy necessary end: Health care proxies need our support.

OBJECTIVE: To promote development of written advance directives and appointment of a proxy for health care by patients who are under the care of a neurologist. BACKGROUND: since 1989, the American Academy of Neurology (AAN) has endorsed but not actively promoted advance directives. In the years since publication of the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment (SUPPORT), much published material has contradicted the notion that creating advance directives offers patients a useful means of extending their autonomy. METHODS: The author reviewed the post-SUPPORT literature, in which numerous articles criticize and others continue to uphold the use of advance directives. He also conducted a pilot study concerning the health care proxy. Additionally, he reexamined his experiences as an ethics consultant, mindful of the medical literature unfavorable to advance directives, to challenge his own opinion that creating directives and appointing a health care proxy are valuable activities for all adults to engage in and for neurologists to promote. RESULTS: Very few articles focus on advance directives and neurology. This literature is not present in neurology specialty journals. Only two of the five neurologists approached by the author were positive about advance directives and collaborated fully in the pilot study. Reviewing his experiences provided the author with numerous examples of the actual or potential usefulness of health care proxies. CONCLUSIONS: Increasing the advance directives literature in neurology specialty journals may lead to the creation of health care documents by more neurologic patients and the development of innovative ways of extending the autonomy of previously competent individuals. The author has recently formed a volunteer organization, Patient Advocates to Preserve Autonomy (PAPA), to increase effectiveness of advance directives. It is hoped that the reservations of some neurologists about advance directives and proxy decision-making may be lessened if they improve their knowledge of the subject and convince themselves that addressing it is one of the obligations attendant on providing "principal care" for many of their patients. The focus initially needs to be on attitudes, rather than methods. However, this pilot project showed that a passive approach is ineffective. A campaign within the AAN to promote advance directives as an aspect of principal care would be helpful. Patients who have lost the capacity to make their own health care decisions often benefit from advance directives and, especially, from having an appointed health care proxy. Those benefits may improve if patient, proxy, and physician are carefully prepared for their roles.

Advance Directives↗
PubMed2001

X-linked lymphoproliferative disease: three atypical cases.

Common variable immunodeficiency (CVID) is the most frequently occurring primary immunodeficiency in both children and adults. The molecular basis of CVID has not been defined, and diagnosis involves exclusion of other molecularly defined disorders. X-linked lymphoproliferative disease (XLP) is a rare disorder in which severe immunodysregulatory phenomena typically follow Epstein-Barr virus (EBV) infection. Boys who survive initial EBV infection have a high incidence of severe complications, including progressive immunodeficiency, aplastic anaemia, lymphoproliferative disease and lymphoma. Survival beyond the second decade is unusual, although bone marrow transplantation can be curative. Until recently reliable diagnostic testing for XLP has not been available, but the identification of the XLP gene, known as SH2D1A, and coding for a protein known as SAP, means that molecular diagnosis is now possible, both by protein expression assays, and mutation detection, although the mutation detection rate in several series is only 55-60%. We describe three male patients initially diagnosed as affected by CVID, one of whom developed fatal complications suggestive of XLP, and all of whom lack expression of SAP. Two out of three have disease-causing mutations in the SAP gene, consistent with published data for XLP. These findings raise the possibility that a subgroup of patients with CVID may be phenotypic variants of XLP. Further studies are necessary to investigate this possibility, and also to clarify the prognostic significance of SAP abnormalities in such patients in the absence of typical features of XLP.

Adolescent↗
PubMed2001

Serological basis for use of meningococcal serogroup C conjugate vaccines in the United Kingdom: reevaluation of correlates of protection.

The antibody data supporting the use of meningococcal serogroup C conjugate (MCC) vaccines in the United Kingdom were generated by serum bactericidal assay (SBA) using rabbit complement (rSBA). This may give higher titers than those obtained with human complement (hSBA), for which the "gold standard" correlate of protection for meningococcal C disease is a titer of > or =4. Comparison of rSBA and hSBA titers in sera from unvaccinated adults with an rSBA titer of > or =8 showed that for 93% (27 of 29) the titer was > or =4 by hSBA, confirming natural protection. Furthermore, sera from MCC vaccinees showed that an rSBA titer of <8 or > or =128 discriminated susceptibility and protection well (85% with rSBA titers of <8 had hSBA titers of <4, and 99% with rSBA titers of > or =128 had hSBA titers of > or =4). However, discrimination was poor in the rSBA titer range 8 to 64, with only 60% having hSBA titers of > or =4. In such cases we propose that protection can be assumed if there is a fourfold rise in titer between pre- and postvaccination sera or if there is a characteristic booster response to a polysaccharide challenge dose with, if available, evidence of antibody avidity maturation or an hSBA titer of result > or =4. Applying these criteria to toddlers, 10 to 40% of whom had titers in the range 8 to 64 after a single dose of MCC vaccine, showed that 94% had a fourfold rise in titer, including 98% of those in the titer range 8 to 64. In addition, of those with titers of <128 post-MCC vaccination, 90% had titers of > or =128 after a 10-microg polysaccharide booster dose, compared with only 7% of unprimed age-matched toddlers given a full 50-microg dose. Furthermore, the increase in geometric mean avidity index pre- and postbooster was independent of post-primary MCC titer. These results indicated that the majority of toddlers with an rSBA titer between 8 and 64, and some of those with an hSBA result of <4, have mounted a protective immune response with the induction of immunological memory.

Adolescent↗
PubMed2001

Colitis in chronic granulomatous disease.

BACKGROUND: Involvement of the gut in chronic granulomatous disease (CGD) has been previously described and colitis highlighted. However, the nature and histopathology of the colitis are unclear and have been thought to be non-specific or similar to Crohn's disease. METHODS: Seven patients with CGD, suffering from gastrointestinal symptoms were prospectively studied. RESULTS: All patients had anaemia; other symptoms were failure to thrive (5/7) and diarrhoea (5/7). Most had microcytic anaemia (5/7), increased platelets (7/7), and increased erythrocyte sedimentation rate (6/6). Endoscopically there was a friable erythematous mucosa in 6/7. The histological features present in all patients consisted of a colitis with paucity of neutrophils, increased numbers of eosinophils, eosinophilic crypt abscesses, pigmented macrophages, and nuclear debris. In some granulomas were present (2/7). CONCLUSIONS: Colitis is a common cause of gastrointestinal symptoms in CGD and is caused by a non-infective inflammatory process. The histology has specific features, which are distinctive from those seen in Crohn's disease.

Anemia↗